Repression of GPRC5A is associated with activated STAT3, which contributes to tumor progression of head and neck squamous cell carcinoma.

BACKGROUND: G protein-coupled receptor family C group 5 member A (GPRC5A), a retinoic acid-inducible gene, is a lung tumor suppressor. Previously, we showed that repression of GPRC5A expression was associated with pathologic differentiation grade of oral squamous cell carcinomas (OSCC) and overexpression of GPRC5A gene inhibited the malignant phenotype in OSCC cells, suggesting that GPRC5A also functions as a tumor suppressor in oral cancer. However, the molecular mechanisms underlying GPRC5A deficiency in head and neck squamous cell carcinoma (HNSCC) are still unclear. METHODS: In this study, we used Western blot analysis and immunohistochemical (IHC) staining to investigate the expression of GPRC5A in both HNSCC cell lines and clinical samples. GPRC5A stable transfectants and their parental HNSCC cells were characterized for their biological activities in anchorage-independent growth. RESULTS: IHC analysis showed that, GPRC5A expression was high in normal tissue, but gradually decreased in oral leukoplakia, a precancerous stage, and greatly suppressed in primary cancer. Repression of GPRC5A was correlated with activated STAT3, which associates with aggressive clinicopathological features in HNSCC patients. Moreover, overexpression of GPRC5A suppressed IL-6-induced-STAT3 activation and inhibited anchorage-independent growth in HNSCC cells. CONCLUSIONS: Repressed GPRC5A associates with increased tumor grade and activated STAT3, which may be used as a prognostic marker for tumor progression of HNSCC.

Role of fine needle aspiration cytology in the differential diagnosis of vascular anomalies from other lesions in the head and neck region.

Objective To summarise the role of fine needle aspiration cytology in the differential diagnosis of vascular anomalies from other lesions in the head and neck region by presenting five interesting cases reported from our hospital data. Method Five patients ranging in age from 3 months to 25 years old were diagnosed with vascular anomalies based on their histories, clinical examinations, imaging examinations and ultrasonic testing. The previous diagnosis of these patients were corrected by fine needle aspiration cytology in our hospital and the proper treatment was administered. Result Two cases were wrongly treated in a local hospital. All five of the patients underwent operations after excluding vascular anomalies by fine needle aspiration cytology. Conclusion Fine needle aspiration cytology should be used in the following situations to prevent misdiagnoses and the mistreatment as vascular anomalies: when imaging examination and ultrasonic testing lead to a diagnosis of vascular malformation, but the history or clinical examination does not confirm this diagnosis; when lesions are treated as "vascular malformations" by sclerotherapy, and the hydatid fluid is not like blood or lymph fluid; and when propranolol is used to treat the proliferation stage of "haemangiomas" with without any effect.

High Vimentin Expression Associated with Lymph Node Metastasis and Predicated a Poor Prognosis in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a common public health problem worldwide with poor prognosis, which is largely due to lymph node metastasis and recurrence. Identification of specific molecular markers of OSCC with lymph node metastasis would be very important for early and specific diagnosis. In this study, we screened for the potential prognosis markers via unbiased transcriptomic microarray analysis in paired two OSCC cell lines, a lymph node metastatic HN12 cell line and a low metastatic parental HN4 cell line. The results showed that vimentin, with 87-fold increase of expression, was on the top of all upregulated genes in metastatic HN12 cells compared to non-metastatic HN4 cells. Treatment of non-metastatic HN4 cells with TGF-ß1 induced epithelial to mesenchymal transition (EMT), with increased vimentin expression as well as enhanced migration activity. Consistently, knockdown of vimentin via siRNA resulted in suppressed invasion and migration activities of HN12 cells, suggesting an essential role of vimentin in EMT-related functions of OSCC cells. Finally, immunohistochemical (IHC) staining analysis showed that high vimentin expression was strongly associated with high lymph node metastases (p < 0.05), and poor overall survival (p < 0.05) in OSCC patients. Thus, high vimentin expression is strongly associated with increased metastatic potential, and may serve as a prediction marker for poor prognosis in OSCC patients.

A retrospective study of six patients with mandibular metastatic carcinoma.

Mandibular metastatic carcinoma is a rare lesion that accounts for <1% of all oral malignancies. To provide greater experience in this field, the present study was conducted in which 6 cases of mandibular metastatic carcinoma were retrospectively reviewed. The origin of the lesions was the prostate in 2 cases, the lungs in 2 cases, the breast in 1 case and the thyroid gland in 1 case. The clinical and computed tomography features, surgical management and follow-up outcomes were investigated. The study indicated that surgeons should include the suspicion of metastasis in the differential diagnosis for mandibular tumor, particularly in patients who have a history of malignancy. A poor prognosis was associated with the examined patients. To extend the survival time as long as possible, a treatment strategy using multiple therapies, including segmental mandibulectomy, radiotherapy and chemotherapy, is recommended.

Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma.

Salivary adenoid cystic carcinoma (SACC) is characterized by invasive local growth and a high incidence of lung metastasis. Patients with lung metastasis have a poor prognosis. Treatment of metastatic SACC has been unsuccessful, largely due to a lack of specific targets for the metastatic cells. In this study, we showed that epidermal growth factor receptors (EGFR) were constitutively activated in metastatic lung subtypes of SACC cells, and that this activation was induced by autocrine expression of epiregulin (EREG), a ligand of EGFR. Autocrine EREG expression was increased in metastatic SACC-LM cells compared to that in non-metastatic parental SACC cells. Importantly, EREG-neutralizing antibody, but not normal IgG, blocked the autocrine EREG-induced EGFR phosphorylation and the migration of SACC cells, suggesting that EREG-induced EGFR activation is essential for induction of cell migration and invasion by SACC cells. Moreover, EREG-activated EGFR stabilized Snail and Slug, which promoted EMT and metastatic features in SACC cells. Of note, targeting EGFR with inhibitors significantly suppressed both the motility of SACC cells in vitro and lung metastasis in vivo. Finally, elevated EREG expression showed a strong correlation with poor prognosis in head and neck cancer. Thus, targeting the EREG-EGFR-Snail/Slug axis represents a novel strategy for the treatment of metastatic SACC even no genetic EGFR mutation.

Long-term results of a randomized phase III trial of TPF induction chemotherapy followed by surgery and radiation in locally advanced oral squamous cell carcinoma.

Previously, we conducted a randomized phase III trial of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy in surgically managed locally advanced oral squamous cell carcinoma (OSCC) and found no improvement in overall survival. This study reports long-term follow-up results from our initial trial. All patients had clinical stage III or IVA locally advanced OSCC. In the experimental group, patients received two cycles of TPF induction chemotherapy (75mg/m2 docetaxel d1, 75mg/m2 cisplatin d1, and 750mg/m2/day 5-fluorouracil d1-5) followed by radical surgery and post-operative radiotherapy; in the control group, patients received upfront radical surgery and post-operative radiotherapy. The primary endpoint was overall survival. Among 256 enrolled patients with a median follow-up of 70 months, estimated 5-year overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival rates were 61.1%, 52.7%, 55.2%, and 60.4%, respectively. There were no significant differences in survival rates between experimental and control groups. However, patients with favorable pathologic responses had improved outcomes compared to those with unfavorable pathologic responses and to those in the control group. Although TPF induction chemotherapy did not improve long-term survival compared to surgery upfront in patients with stage III and IVA OSCC, a favorable pathologic response after induction chemotherapy may be used as a major endpoint and prognosticator in future studies. Furthermore, the negative results observed in this trial may be represent type II error from an underpowered study. Future larger scale phase III trials are warranted to investigate whether a significant benefit exists for TPF induction chemotherapy in surgically managed OSCC.

Prognostic factors in pterygopalatine and infratemporal fossa malignant tumours: A single institution experience.

PURPOSE: To elucidate the clinical characteristics of malignancies involving the pterygopalatine and infratemporal fossa and identify the outcome-related predictors. METHODS: A retrospective review of the patients diagnosed with malignancies involving these spaces between 2006 and 2013 was conducted. We investigated the 5-year recurrence free survival, metastasis free survival and overall survival, and univariate and multivariate analysis were used to identify the outcome-related factors. RESULTS: A total of 80 patients (46 male and 34 female) aged from 1 to 82 years were retrospectively analysed. The most frequent location for involved malignancies included the pterygopalatine fossa (n = 35, 43.8%), followed by the infratemporal fossa (n = 25, 31.2%) and the pterygopalatine and infratemporal fossa together (n = 20, 25%). In multivariate analysis, gender (HR: 2.59, 95% CI: 1.034-6.488, p = 0.042), margin status (HR: 6.158, 95% CI: 2.115-17.932, p = 0.001) and adjuvant radiotherapy (HR: 3.116, 95% CI: 1.057-9.191, p = 0.039) were predictors for the 5-year recurrence-free survival rate, and brain invasion (HR: 6.218, 95% CI: 1.375-28.115, p = 0.018) and surgical margin (HR: 21.961, 95% CI: 2.383-202.418, p = 0.006) were predictors for the 5-year overall survival rate. CONCLUSION: These results indicate that malignancies involving the pterygopalatine and infratemporal fossa have a poor prognosis. Brain invasion is a dangerous sign for decreased survival. An ideal surgical margin is associated with a lower recurrence and higher survival rate. Adjuvant radiotherapy should be performed to achieve better local control.

Congenital huge submandibular and neck teratoid cyst in newborn.

Head and neck teratoid cysts are the least common congenital cysts in the head and neck region, accounting for approximately 1.8% of all dermoid cysts. Teratoid cysts exhibiting mesodermal elements may be lined by gastric, intestinal, respiratory, squamous, or cilitated epithelium. We present a case of huge submandibular and neck teratoid cyst in newborn with airway obstruction and feeding difficulty. Surgical extirpation is the treatment of choice. However, before operation, some other cystic diseases in the head and neck region needs to be excluded. Fine-needle aspiration biopsy was necessary in differential diagnosis of lesions before treatment, especially that the principle of treatment of those diseases is different.

Clinical application of the dorsalis pedis free flap for reconstruction of oral cancer defects.

PURPOSE: The purposes of this study were to evaluate the clinical application and efficacy of the dorsalis pedis fasciocutaneous flap in the reconstruction of oral cavity defects and to assess the associated donor-site morbidity. PATIENTS AND METHODS: From September 2009 to December 2012, 7 patients with associated oral cavity defects resulting from tumor resection underwent reconstruction with a dorsalis pedis fasciocutaneous flap. Surgical anatomy and harvesting procedure of the dorsalis pedis flap are described. Special consideration was given to the associated donor-site morbidity. RESULTS: All flaps survived without any complications. All 7 flaps were based on the dorsalis pedis artery and the greater saphenous vein for perfusion and drainage respectively. In all 7 cases, the donor site was closed with a full-thickness skin graft, with no associated healing complications or functional deficit of the foot. The resulting scar was well hidden in the lower extremity. CONCLUSIONS: The dorsalis pedis fasciocutaneous flap is a thin and pliable flap sharing many similarities with the radial forearm flap, thus making it ideal for intraoral reconstruction. Proper intraoperative and postoperative care of the donor site can result in minimal morbidity, as shown in this study. This flap may provide an ideal alternative to the radial forearm free flap, with the added advantages of a well-hidden scar and a high level of patient satisfaction.

Application of modified Karapandzic flaps in large lower lip defect reconstruction.

PURPOSE: Reconstruction of a lower lip defect with a Karapandzic flap often leads to greater rounding of the commissure. The aim of this study was to provide a new design of bilateral Karapandzic flap for large lower lip defect reconstruction. MATERIALS AND METHODS: In this case-series retrospective study, a modification of the Karapandzic lip reconstruction technique was used with an additional incision to obtain more tissue. The esthetic outcome of the reconstruction was assessed using a 4-point scale with regard to the shape of the commissure, lip symmetry, appearance of the scar, and lip projection. Functional outcome was assessed by speech, preservation of oral competence, lip sensation, facial expression, diet, and denture usage. RESULTS: Seventeen patients (13 male, 4 female; age range, 52 to 82 yr) with squamous cell carcinoma in the lower lip underwent single-stage lip reconstruction. Lip defects after tumor resection ranged from 50 to 90% of the lower lips. All patients achieved oral competence, without leading to greater rounding of the commissure. The esthetic outcome was considered good to excellent in 88% of cases and reconstruction did not lead to functional impairments in speech, oral competence, lip sensation, facial expression, diet, or denture usage. CONCLUSIONS: The modified bilateral Karapandzic flap is a reliable technique to reconstruct large lip defects without leading to rounding of the commissure. With this technique, good esthetic and functional outcomes can be achieved.

Immediate reconstruction of soft palate defects after ablative surgery and evaluation of postoperative function: an analysis of 45 consecutive patients.

PURPOSE: The aim of the present study was to estimate the effect of different defect sizes and flaps used on the postoperative soft palate functional outcomes. PATIENTS AND METHODS: The study included 45 consecutive patients who were treated by 3 different reconstructive flaps for their soft palate defect. Postoperative speech and swallowing functions were assessed to measure the relationships between the defect size and postoperative function of the soft palate, the different flap reconstructions, and postoperative function. The 1-way analysis of variance test was computed. P < .05 was considered significant. RESULTS: The postoperative evaluation revealed that both speech and swallowing functions were normal or near normal in patients with type II defects, but they were poor in the patients with type III and IV defects. No significant changes in postoperative soft palate function using different flap sizes for the same defect type were found. CONCLUSIONS: The study results have confirmed that the size of the defect, rather than the type of the flap, will have the most critical influence on soft palate postoperative function. A defect size of 50% or less will have a better outcome than defect sizes greater than 50%.

Tricholemmal carcinoma of the head and neck region: A report of 15 cases.

Tricholemmal carcinoma is an extremely rare malignancy of the skin, and its biological behavior and management is controversial. The objective of the present study was to investigate the clinicopathological characteristics and management of tricholemmal carcinoma of the head and neck region. The study analyzed 15 patients with tricholemmal carcinoma. Demographic and clinical data were collected, and features associated with the management and prognosis of tricholemmal carcinoma were analyzed. Two of the 15 patients were lost to follow-up. The results showed that, during the follow-up period, 5 of the 13 available patients succumbed to the causes of recurrence (n=3), neck lymph node metastasis (n=1) and Parkinson's disease (n=1). No patients developed distant metastasis. The disease-free survival (DFS) and overall survival (OS) were 31.1±7.8 and 32.9±7.4 months (mean ± SE), respectively, and the DFS and OS rates were 69.2 and 61.5%, respectively. In conclusion, the biological behavior of tricholemmal carcinoma is locoregionally aggressive. The recommended management for head and neck tricholemmal carcinoma is radical resection and neck dissection, and post-operative radiotherapy may be considered for high-risk patients.

Tongue reconstruction with tongue base island advancement flap.

Reconstruction of a medium-sized defect of the tongue remains a challenge if aesthetic impairment is to be avoided. In this study, 19 tongue base island advancement flaps were developed to reconstruct medium-sized defects after the tongue squamous cell carcinoma ablations: 13 cases were T1N0M0, and 6 cases were T2N0∼1M0. The largest size amounts to 5.4 × 4.8 cm (length × width), with a mean of 4.6 × 4.4 cm. The tongue base island advancement flap reduces the volume of the tongue base without causing function impairment of the tongue. All patients recovered with good objective and subjective speech and swallowing and aesthetics. No patient developed local recurrence or lymphatic metastasis. The technique of tongue base advancement flap is ideal for functional and aesthetic repair of medium-sized tongue defects after cancer ablation.

[Polymorphous low-grade adenocarcinoma of the palate with cervical lymph node and distant metastasis: report of one case and review of the literature].

Polymorphous low-grade adenocarcinoma is a rare salivary gland tumor with lower rate of local and regional metastasis and rare distant metastasis. The prognosis is relatively good. This paper reported a case of palatal polymorphous low-grade adenocarcinoma with cervical lymph node and distant metastasis, and discussed clinical characteristics, differential diagnosis, treatment, prognosis based on literature review.

Dose dependent activation of retinoic acid-inducible gene-I promotes both proliferation and apoptosis signals in human head and neck squamous cell carcinoma.

The retinoic-acid-inducible gene (RIG)-like receptor (RLR) family proteins are major pathogen reorganization receptors (PRR) responsible for detection of viral RNA, which initiates antiviral response. Here, we evaluated the functional role of one RLR family member, RIG-I, in human head and neck squamous cell carcinoma (HNSCC). RIG-I is abundantly expressed both in poorly-differentiated primary cancer and lymph node metastasis, but not in normal adjacent tissues. Activation of RIG-I by transfection with low dose of 5'-triphosphate RNA (3p-RNA) induces low levels of interferon and proinflammatory cytokines and promotes NF-κB- and Akt-dependent cell proliferation, migration and invasion. In contrast, activation of RIG-I by a high dose of 3p-RNA induces robust mitochondria-derived apoptosis accompanied by decreased activation of Akt, which is independent of the interferon and TNFα receptor, but can be rescued by over-expression of constitutively active Akt. Furthermore, co-immunoprecipitation experiments indicate that the CARD domain of RIG-I is essential for inducing apoptosis by interacting with caspase-9. Together, our results reveal a dual role of RIG-I in HNSCC through regulating activation of Akt, in which RIG-I activation by low-dose viral dsRNA increases host cell survival, whereas higher level of RIG-I activation leads to apoptosis. These findings highlight the therapeutic potential of dsRNA mediated RIG-I activation in the treatment of HNSCC.

Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma.

PURPOSE: To evaluate induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) followed by surgery and postoperative radiotherapy versus up-front surgery and postoperative radiotherapy in patients with locally advanced resectable oral squamous cell carcinoma (OSCC). PATIENTS AND METHODS: A prospective open-label phase III trial was conducted. Eligibility criteria included untreated stage III or IVA locally advanced resectable OSCC. Patients received two cycles of TPF induction chemotherapy (docetaxel 75 mg/m(2) on day 1, cisplatin 75 mg/m(2) on day 1, and fluorouracil 750 mg/m(2) on days 1 to 5) followed by radical surgery and postoperative radiotherapy (54 to 66 Gy) versus up-front radical surgery and postoperative radiotherapy. The primary end point was overall survival (OS). Secondary end points included local control and safety. RESULTS: Of the 256 patients enrolled onto this trial, 222 completed the full treatment protocol. There were no unexpected toxicities, and induction chemotherapy did not increase perioperative morbidity. The clinical response rate to induction chemotherapy was 80.6%. After a median follow-up of 30 months, there was no significant difference in OS (hazard ratio [HR], 0.977; 95% CI, 0.634 to 1.507; P = .918) or disease-free survival (HR, 0.974; 95% CI, 0.654 to 1.45; P = .897) between patients treated with and without TPF induction. Patients in the induction chemotherapy arm with a clinical response or favorable pathologic response (≤ 10% viable tumor cells) had superior OS and locoregional and distant control. CONCLUSION: Our study failed to demonstrate that TPF induction chemotherapy improves survival compared with up-front surgery in patients with resectable stage III or IVA OSCC.

Buccal reconstruction with the mouth floor mucosal flap.

A mouth floor mucosal flap was developed to reconstruct medium-sized intraoral buccal defects, too large for primary closure if major functional and aesthetic impairment is to be avoided. Although free flaps, perforator flaps, or even skin grafts can be designed for buccal reconstruction, they may not provide good mucosal sensitivity, motility, volume, and texture to replace lost structures with similar tissue. Moreover, secondary morbidity can be avoided with this adjacent flap.In our study, 8 flap reconstruction procedures were performed from March 2009 to July 2011: 4 cases of leukoderma, 2 cases of buccal cancer (T1 N0 M0), and 2 cases of papillary epithelioma. The largest size amount to 5.3 × 3.8 cm (length × width), with a mean of 4.3 × 3.4 cm. Compared with free flaps (forearm arm flap for example) for buccal reconstruction, application of the mouth floor flap has its indications. First, to secure the motility of tongue and function of mouth opening, the upper bound of the defects was below the occlusion line. Generally, the width between top and bottom was less than 4 cm. Second, at least a partial buccinator muscle can be preserved after lesion resection and then facial collapse can be avoided. Third, patients had molar absence or relevant teeth had to be extracted during surgery.All patients recovered from intraoral surgeries with good objective and subjective speech and swallowing and aesthetics and without injury to the lingual nerve, the submandibular gland duct, and the sublingual gland. Results indicate that the mouth floor mucosal flap is reliable and technically easy for reconstructing medium-sized intraoral buccal defects, with good function and aesthetics with little secondary morbidity.

Gorham disease in the maxilla.

Gorham disease is a rare condition that is characterized by the proliferation of thin-walled vascular channels associated with regional osteolysis. The exact etiology of Gorham disease is unknown. The diagnosis of Gorham disease is based on clinical, radiological, and histological features after excluding osteolysis, which is secondary to other pathologic processes. Those pathologic processes include congenital, metabolic, neoplastic, and immunologic etiologies and infections. The appearance of the disease in the craniofacial region often involves the mandible. In the reported literature (English language only), there is 1 reported case of the disease located in the maxilla alone. In this study, we present another case of Gorham disease that presents in the maxilla of a 37-year-old man.

CCND1 as a predictive biomarker of neoadjuvant chemotherapy in patients with locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Cyclin D1 (CCND1) has been associated with chemotherapy resistance and poor prognosis. In this study, we tested the hypothesis that CCND1 expression determines response and clinical outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC) patients treated with neoadjuvant chemotherapy followed by surgery and radiotherapy. METHODOLOGY AND FINDINGS: 224 patients with HNSCC were treated with either cisplatin-based chemotherapy followed by surgery and radiotherapy (neoadjuvant group, n = 100) or surgery and radiotherapy (non-neoadjuvant group, n = 124). CCND1 expression was assessed by immunohistochemistry. CCND1 levels were analyzed with chemotherapy response, disease-free survival (DFS) and overall survival (OS). There was no significant difference between the neoadjuvant group and non-neoadjuvant group in DFS and OS (p = 0.929 and p = 0.760) when patients treated with the indiscriminate administration of cisplatin-based chemotherapy. However, in the neoadjuvant group, patients whose tumors showed a low CCND1 expression more likely respond to chemotherapy (p<0.001) and had a significantly better OS and DFS than those whose tumors showed a high CCND1 expression (73% vs 8%, p<0.001; 63% vs 6%, p<0.001). Importantly, patients with a low CCND1 expression in neoadjuvant group received more survival benefits than those in non-neoadjuvant group (p = 0.016), however patients with a high CCND1 expression and treated with neoadjuvant chemotherapy had a significantly poor OS compared to those treated with surgery and radiotherapy (p = 0.032). A multivariate survival analysis also showed CCND1 expression was an independent predictive factor (p<0.001). CONCLUSIONS: This study suggests that some but not all patients with HNSCC may benefit from neoadjuvant chemotherapy with cisplatin-based regimen and CCND1 expression may serve as a predictive biomarker in selecting patients undergo less than two cycles of neoadjuvant chemotherapy.

Clinical management of peripheral ameloblastoma.

Peripheral ameloblastoma is a rare epithelial odontogenic tumor, limited to the soft tissues of the gingiva or oral mucosa. Peripheral ameloblastoma represents approximately 2% to 10% of all ameloblastomas. It is always considered to be benign, but occasionally it may be locally aggressive or with malignant potential. In this article, we report 3 new cases of benign peripheral ameloblastoma and further discuss the clinical management of this disease.